Editorial: Immunometabolism in immunological tolerance and regulation: novel mechanisms and clinical interventions

The immune system continuously integrates environmental cues, antigenic stimulation, and tissue-specific signals to maintain the balance between immune activation and tolerance. While classical immunology has traditionally focused on receptor signaling pathways and transcriptional regulatory networks, increasing evidence indicates that metabolic circuits represent a fundamental regulatory architecture underlying immune cell function. The emerging field of immunometabolism therefore investigates how metabolic pathways intersect with immune signaling to shape immune responses. In this context, immune tolerance, which is once considered a passive consequence of immune suppression, is now recognized as an actively maintained state constrained by metabolic programs.Here in this Research Topic, we propose a conceptual framework in which immune tolerance is governed by interconnected immunometabolic checkpoints operating at multiple biological levels. These checkpoints encompass intrinsic metabolic programs within immune cells, metabolic conditions within tissue microenvironments, and systemic metabolic regulation together with emerging technological advances.Together, these interconnected immunometabolic checkpoints form a regulatory architecture that governs immune homeostasis across cellular, tissue, and systemic contexts.At the most cellular level, immune tolerance is shaped by metabolic programs operating within immune cells. Distinct immune cell states are closely associated with characteristic metabolic configurations, including effector activation, functional exhaustion, and regulatory phenotypes. Within the adaptive immune system, T cell subsets exhibit specialized and functionally requisite metabolic configurations.Regulatory T cells (Tregs) rely on metabolic programs centered on mitochondrial oxidative phosphorylation and fatty acid oxidation to maintain stability and suppressive capacity, illustrating how metabolic flexibility underpins sustained immune tolerance.Conversely, in pathological states such as severe COVID-19, aberrant metabolic reprogramming in effector T cells is directly linked to dysfunction. The expansion of activated CD38+HLA-DR+ T cell subsets is associated with NAD+ metabolism dysregulation, which correlates with their exhausted phenotype and poor clinical prognosis, highlighting how metabolic disruption can precipitate a loss of functional competence.This principle extends to innate immunity. For instance, the polarization of macrophages into pro-inflammatory (M1) or anti-inflammatory/repair (M2) phenotypes is governed by distinct metabolic shifts, with mitochondrial integrity and related genes being critical for directing this functional switch, as evidenced in chronic inflammatory diseases.Collectively, these findings establish that intrinsic immunometabolic checkpoints are pivotal in determining whether an immune response progresses towards inflammatory escalation, stabilizes into a regulatory tolerant state, or devolves into dysfunctional exhaustion. Thus, immune tolerance arises not solely from intracellular metabolic programs but from the dynamic integration of immune signaling with the metabolic architecture of tissues.